Isoquinoline compounds and derivatives thereof



Patented Aug. 8, 1939 UNITED STATES PATENT OFFICE TISOQUIINOLINE COMPOUNDS AND DERIVA TIVES THEREOF No Drawing. Application December 9, 1937, Se-

rial No. 178,883. In Germany December 12,

4 Claims. (01. 260289) The present invention relates to isoquinoline compounds containing a hydroaromatic radical in l-position and to the derivatives thereof hydrogenated in the pyridine nucleus.

It is known that isoquinolin-e compounds having an organic radical in l-position and the derivatives thereof hydrogenated in the pyridine ring are valuable physiologically active substances which in part are used in medicine. Isoquinoline compounds containing a hydroaromatic radical in l-position have hitherto been unknown.

Now we have found that isoquinoline compounds of the latter kind are obtained by condensing, according to methods known for 'making isoquinoline compounds substituted in 1- position, an aromatic-aliphatic 1-aryl-2-aminoethane compound with a hydroaromatic acid, acid derivative or aldehyde, subjecting the condensation product so obtained to ring closure, advantageously after hydrogenation, and, if necessary, hydrogenating or dehydrogenating the isoquinoline compound so obtained. When starting, for instance, from aromatic-aliphatic aminoalcohols of the formula RCI-IOHCH2NI-I2 (wherein R stands for aryl) or the ethers or homologues or analogues thereof, the corresponding amides are obtained by condensation with hexahydrobenzoic acids (chlorides, esters, etc.), which amides are converted into the 1- cyclohexyl-isoquinoline derivatives by means of acid condensing agents such as phosphorus oxychloride or the like. When starting from the corresponding amino-ketones the ketone-group is hydrogenated, preferably after the formation of the amide. When starting from aromaticaliphatic amines of the formula (wherein R stands for aryl) in carrying out the invention, the corresponding 3:4-dihydro-isoquinoline compounds are obtained which may be hydrogenated to the corresponding tetrahydro-compounds or dehydrogenated to the isoquinoline compounds. With the same good result the new isoquinoline derivatives may also be produced according to one of the processes known for obtaining isoquinolines, for instance, by condensing the aforesaid amines with hydroaromatic aldehydes and subjecting the condensation products thus obtained to ring closure to form the corresponding tetrahydro-isoquinoline which, if necessary, may be dehydrogenated in the pyridine nucleus. Instead of using saturated hydroaromatic. acids the process of the present invention may be carried out with acids which are only partially hydrogenated in the nucleus. In this case it may be advantageous to produce the nuclear double linkage subsequently by starting, for instance, from hexahydro-hydroXy-acids and splitting off water from the condensation products.

With the same or similar result the process of the present invention may also be carried out with hydroaromatic acids in which an aliphatic residue is contained between the nucleus and the carboxyl group. Thus, for instance, from cyclohexylacetic acid the corresponding hexahydrobenzyl-isoquinoline compounds are obtained.

The new compounds have the following general formula:

wherein both X's jointly stand for one of the following groupings:

wherein R stands for cyclohexyl, cyclohexenyl or he'xahydrobenzyl, Y stands for hydrogen, alkyl or cyclohexyl, Z1 and Z2 each stand for hydrogen, hydroxy, alkoxy, or Z1 and Z2 together stand for alkylenedioxy. l v

' The compounds aresolid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.

The new products have valuable characteristics from various aspects:

Thus the 1-cyclohexyl-6 :7-dimethoxyisoquinoline is twice as effective spasmolitically as papaverine. The l-cyclohexenyl-Al-G:Z-dimethoxyisoquinoline has in the gall-bladder twice the activity and in the intestines four times the activity of papaverine. The l-cyclohexyl-Gz'I-dimethoxydihydro(3:4)-isoquinoline has a strong central-stimulating effect.

It may furthermore be noted that the hydrogenated acids used as' parent materials are in part very readilyaccessible, and cheap parent materials for the production of isoquinoline compounds of the type named, hereas thealkoxyphenylacetic acids required for the production of papaverine and its homologues can only be made in a complicated manner. The compounds obtainable according to the present invention are intended for use in part as pharmaceutical prodnets and in part for the manufacture of other remedies.

The following examples serve to illustrate the invention, but they are not intended to limit it thereto:

1 1 -cycZohex' l-6 :7 -dimethoxyisoquznoline 32.1 grams mol.) of N-h'exahydrobenzoyl- B- (3 i4-dimethoxyphenyl) -B methoxyethylamine (melting point 105 C. to 106 C.) are heated for 2 hours in a reflux apparatus in 300 cc. of dry chloroform with 50 cc. of phosphorus oxychloride. The solvent is then distilled under reduced pressure and the residue is repeatedly extracted with hot water containing hydrochloric acid. The acid solution is extracted with ether in order to remove smeary constituents, then rendered alkaline by means of alkali solution and again extracted with ether. After the ethereal extract has been dried with potassium carbonate and the ether has been evaporated the 1-cyclohexyl-6z7- dimethoxyisoquinoline of the formula crystallises. It may be purified by repeated recrystallisation from petroleum ether or ether, or better by distillation under a highly reduced pressure. It boils under a pressure of 0.04 millimeter at a temperature of 176 C. to 180 C. The melting point is 106.5 C. to 107 C.

The acid amide used as parent material can be obtained by causing 2 molecular proportions of 3:4-dimethoxyphenyl-methoxyethylamine to react with 1 molecular proportion of hexahydrobenzoyl chloride in dry benzene.

2. 1 A1 -cyclohe:cenyl- 6 :7 -dimethoxyisoquinoline (a) 31.9 grams mol.) of N-tetrahydrobenzoyl-p- (3 :4-dimethoxyphenyl) 43- m-ethoxyethylamine (melting point C. to 81 C.) in 300 cc. of dry chloroform are boiled for 2 hours with 50 cc. of phosphorus oxychloride and the product is worked up as described in Example 1. The base of the formula CHKO\ N CHaO distils at 165 C. to 170 C. under a pressure of 0.02 millimeter; its melting point is 107 C. to 109 C.

(b) 33.7 grams 6 mol.) of N-hexahydro-Z- hydroxybenzoyl- 13 -(3:4 dimethoxyphenyl) [i methoxyethylamine (melting point 123 C. to

3. 1 -hexahydrobenzyZ-6 :7 -dimethozcyisoquinoline 33.5 grams (:9 mol.) of N-hexahydrophenylacetyl- 5 -(3:4 dimethoicyphenyl) p -methoxyethylamine (melting point 99 C. to 100 C.) in 250 cc. of xylene are boiled for half an hour with 70 cc. of phosphorus oxylchloride. After working up in the usual manner and recrystallisation from petroleum ether there is obtained the compound of the following formula:

CHaO

cnao

Hr- H:

Hz- H1 The melting point of the product is 104 C. to 105 C.

4. I-cyCZOhexyZ-G:7-diethoxyisoquinoline 36.3 grams mol.) of N-hexahydrobenzoyl-fi- (3 :4-diethoxyphenyl) -fi-ethoxyethylamine (melting point 109 C. to 110.5 C.) in 250 cc. of benzene are boiled for 3 hours with 50 cc. of phosphorus oxychloride. After recrystallisation three times from petroleum ether and once from ether the compound of the formula has a melting point of 83 C. to 84 C.

5. 1-cyclohea:yZ-6:7-ethylenediomyisoquinoline 10.3 grams of N-hexahydrobenzoyl-B-(3:4- ethylenedioxyphenyl)-{3-methoxyethylamine in 100 cc. of dry benzene are heated for 3 hours in a reflux apparatus with 15 cc. of phosphorus oxychloride. The base of the following formula onro melts at 97 C. to 98 C.

6. 1 -cyclohe.'cyl-3 :4 -dihydro- 6 :7 -dimethomyisoquinoline 11.5 grams of N-hexahydrobenzoyl-B:4-dimethoxyphenylethylamine (melting point 111 C. to 111.5 C.) in 55 cc. of dry choroform are boiled for 5 hours with 16 cc. of phosphorus oxychloride and the product is worked up as described in Example 1. The product of the formula so obtained melts at 79.5 C. to C. after recrystallization three times from petroleum ether.

7. 1-cyclohexyl-3 :4-dihg1dro-6:7-ethylenediowyisoquinoline 9 grams of N-hexahydrobenzoylethylenedioxyphenylethylamine (melting point 129.5 C.) in 50 cc. of dry chloroform are boiled for 5 hours in a reflux apparatus with 12 cc. of phosphorus oxychloride. There is obtained the product of the formula which melts at 106.5 C. to 107 0. when twice recrystallized from ether.

The 3:4-ethylenedioxyphenylethylarnine may be obtained from the corresponding styrene by catalytic reduction according to Kindler, Annalen, vol. 511, page 209 (1935). It boils at 167 C. to 169 C. under a pressure of 14 millimeters.

8. 1-cycZohexyl-3:4-dihydro-6-meth0wy-7-hydrozryisoquinolme 6.4 grams of N-hexahydrobenzoyl-B (3-methoxy 4 hydroxyphenyl) ethylamine (melting point 123.5 C. to 124.5 C.) in 33 cc. of chloroform are heated for2 hours in a reflux apparatus with 8 cc. of phosphorus oxychloride. The solvent is evaporated under reduced pressure and the residue is taken up withhotwater,

C. and under pressure.

filtered from undissolved resin and the solution is then extracted with benzene in order to remove non-basic constituents. The aqueous solution is then rendered alkaline while cooling by means of concentrated potassium carbonate solution and extracted with ether. After drying for a short time with potassium carbonate the hydrochloride of the desired base is precipitated by means of alcoholic hydrochloric acid. This salt which is first obtained in a smeary state is obtained in a powdered state by repeated trituration' alternately with ether and petroleum ether; it may be recrystallized from a mixture of isopropyl alcohol and acetone. The compound has the formula 2 OHaO &/

and a melting point of 148 C. to 149 C. The substance yields a dirty green color with ferric chloride solution.

9; 1 cycZohexyZ-6 :7 -dimethoxyisoquinoline (a) 13.1 grams of 1-cyclohexyl-3:4-dihydro- 6:7-dimethoxyisoquinoline (of. Example 6), in a. pure state, are hydrogenated with palladium at 50 C. in 50 cc. of N-hydrochloric acid and 300 cc. of water. After about 4 hours the absorption of hydrogen is complete. The whole is then filtered from the catalyst and concentrated under reduced pressure, whereby the hydrochloride of the new compound of the formula CHaO 2 NH cmo Hr H3 crystallizes. It may be purified by recrystallization from alcohol and then melts at 228 C. to 230 C. after previously sintering at C. to C.

(b) 13.6 grams of l-cyclohexyl-G:7-dimethoxyisoquinoline are hydrogenated with nickel in 50 cc. of N-hydrochloric acid and 300 cc. of water at After having been worked up as described under (a) there is likewise obtained the compound of the formula given above, which melts at 228 C. to 230 C.

11. 1-A1-cyclohexenyl-3-methyl-6.7 dimethoatyisoquinoline 6.1 grams of N-Al-tetrahydrobenzoyl-(3:4-dimethoxyphenyl) -2-aminopropanol (melting point 134 C. to C.) in 60 cc. of chloroform are boiled for 4 hours in a reflux apparatus with 12 cc. of phosphorus oxychloride. After working up in the usual manner the base is distilled under a highly reduced pressure. It boils at 172 C. to C. under 0.01 millimeter pressure. The distilled product is taken up in ether and from this solution the hydrochloride of the base is precipitated by means of ethereal hydrochloric acid. After triturating several times with dry acetone the salt of the base of the formula is obtained in a solid form. It melts at 207 C. to 208 C. after recrystallisation from. a mixture of isopropyl alcohol and acetone.

12. 1 A 1-cyZ0hexenyl-3-cycloheazyl-fi:T-dimethoxyisoquinoline 2.4 grams of N-tetrahydrobenzoyl-p-(3:4-dimethoxyphenyl) -[i hydroxy-u-cyclohexylethylamine (melting point 158 C. to 159 C.) in 20 cc. of dry benzene are boiled for 4 hours with 5 cc. of phosphorus oxychloride. After working up in the usual manner the crude base is dissolved in absolute ether and the hydrochloride of the base of the formula is precipitated therefrom by means of ethereal hydrochloric acid.

The 3:4 dimethoxyphenylhydroxycyclohexylethylamine used as parent material may be prepared in the following manner:

From veratrol and hexahydrophenylacetyl chloride there is obtained according to the F'riedel- Crafts reaction the 3:4-dimethoxyphenylhexahydrobenzyl ketone of melting point 52 C. to 53 C. This yields with butyl nitrite an isonitrosocompound of melting point of 145 C. to 147 C., from which the desired amine may be prepared with palladium and hydrogen in an alcoholic hydrochloric acid solution; the hydrochloride of the amine melts at 208 C. to 210 C.

1 3. 1 -cyclohemyZ-6 :7 -dz'methoxyis0quinoline 15 grams of 1-cyclohexyl-6z7 -climethoxytetrahydroquinoline are heated for 15 hours in a reflux apparatus with 70 'cc. of xylene and 2 grams of palladium. After the reaction product has been worked up and redissolved from ether there is obtained the 1 cyclohexyl 6:7 dimethoxyisoquinoline described in Example 1 which melts at 106.5 C. to 107 C.

1 4. 1 -cycZohea:yl-3 :4 -dz'hydroisoquinoline 28.4 grams of hexahydrobenzoic acid methylester and 31.4 grams of phenylethylamine are kept for 8 hours at a temperature of C. to C. The reaction product is dissolved in benzene and shaken out with dilute hydrochloric acid. After partially distilling the benzene and adding petroleum ether crystals are precipitated which melt at 93 C. to 94 C. when recrystallized from hexahydrobenzene.

10 grams of the amide so obtained are boiled for '7 hours in a reflux apparatus with 50 cc. of xylene and 15 cc. of phosphorus oxychloride. After distilling the solvent the residue is treated with ether and the ethereal solution is shaken with hydrochloric acid. The isoquinoline product is separated from the hydrochloric acid solution by means of alkali. The base of the formula distils at 145 C. to 150 C. under 4.5 millimeters pressure. The hydrochloride has a melting point of 146 C. to 147 C.

We claim:

1. As new compositions of matter the compounds of the following formula:

wherein both Xs jointly stand for one of the groupings selected from the group consisting of R being a member of the group consisting of cyclohexyl, cyclohexenyl and hexahydrobenzyl, and Y being a member of the group consisting of hydrogen, alkyl and cyclohexyl, Z1 and Z2 each stand for a member of the group consisting of hydrogen, hydroxy and alkoxy, and compounds of the above general formula wherein both Xs have the same meaning as given above and Z1 and Z2 jointly stand for alkylenedioxy, said compounds being solid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.

2. As a new composition of matter the compound of the following formula:

said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.

4. As a new composition of matter the compound of the following formula: 5

E: 01130 )w m said compound being a solid colorless substance H which is readily soluble in benzene, chloroform, ether and petroleum ether. H H,

3. As a new composition of matter the compound of the following formula: H,

CHaO

said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.

MAX BOCKMI jI-IL. HANS HERMANN. 

